‘Sex Bias’ in lupus: Researchers focus on a gene

An autoimmune disease which attacks tissues and organs and which can inflame joints, lupus afflicts women nine times as often as it does men. This “sex bias,” as Jean-Charles Guéry, of France’s national medical research institute Inserm, calls it, has long been known. The role which the gene TLR7 plays has been well-established in mouse research, and there has been a lot of research about the impact of that gene, which is carried on X chromosomes and plays an important role in the body’s immune responses, on lupus rates in men and women.

What hadn’t been demonstrated, Guéry told CreakyJoints, was the demonstration in human immune cells of the hypothesis that the lupus sex bias might derive from TLR7 evading inactivation in X chromosomes. Guéry and colleagues did just that in a paper recently published in Science Immunology, in which they also focused on men with Klinefelter’s syndrome, who are born with an extra X chromosome.

“We demonstrate that the TLR7 gene encoded on the X chromosome escapes normal inactivation in women and individuals with Klinefelter’s syndrome, who thus have two active copies of the gene versus only one in men,” Guéry said in the interview. “Because increased TLR7 is a known risk factor in lupus, we propose that higher TLR7 dosage arising from X-inactivation escape connects the presence of two X chromosomes in females and Klinefelter’s syndrome individuals with the greater risk of developing lupus.”

TLR7 are receptors for nucleic acid (RNA), which occupy cavities within immune cells, such as B cells, which produce antibodies, Guéry explained. Under normal circumstances, TLR7 can “sense” RNA viruses, and thus perform a vital task in the process of antibody development and response against those viruses. But patients suffering from lupus, or other autoimmune diseases, such as psoriasis or Sjögren’s syndrome, can have their TLR7 activated, which then attacks healthy cells, according to Guéry.

“TLR7 is probably extremely important in human life, as mutations resulting in the absence of TLR7 protein expression or function have never been identified so far,” Guéry said. “This attests to the essential role of TLR7 in host survival to viral infection.”

TLR7 is known, when overexpressed by B cells in mice, to lead to lupus development, notes the Inserm website. Although the gene is supposed to be inactivated on one of the X chromosomes in women, it can evade inactivation in many women and certain men. Given the inactivation of the expression of genes on women’s second X chromosome and given that X chromosomes carry TLR7, Guéry and colleagues wondered if women are predisposed to lupus because the gene escapes inactivation, the Inserm site notes.

“Known as TLR7, the gene normally would be inactivated along with other genes on one of the two X chromosomes women carry,” it adds. “However, in some immune cells of healthy women and in men with an extra X chromosome (Klinefelter syndrome, associated with higher incidence of lupus), both copies of the TLR7 gene turned on.” Men with Klinefelter syndrome are also predisposed to lupus — and at much higher rates than other men, notes STAT News.

“Given all the genes that escape X inactivation, there might be others,” said Hal Scofield, of the arthritis and clinical immunology research program at Oklahoma Medical Research Foundation, in an interview with STAT. “You might find others that interact with TLR7,” he added. “You might find a whole cascade.”

Guéry and colleagues will investigate how to target TLR7, with the hopes of limiting the threat or lupus, as well as other diseases.

“In addition to shedding light on SLE and, more broadly, autoimmune diseases, these results could provide valuable information for other autoimmune disorders involving TLR7, or HIV infection, to which men and women respond differently,” said Guéry, on the Inserm site.